The poor regenerative ability of axons in the adult mammalian central nervous system (CNS) underlies the limited functional recovery following spinal cord injury, traumatic brain injury, white matter stroke and certain neurodegenerative disorders. There are two forms of injury-induced axonal growth that may contribute to functional repair: regeneration of injured axons and compensatory growth (or sprouting) of uninjured axons. The goal of this application is to gain a better understanding of the role of the molecular players - both extrinsic factors in the CNS environment and intrinsic factors in the neurons - in axon sprouting and regeneration. The study will focus on two inhibitors of axon growth made by the CNS myelin (Nogo, OMgp) and PTEN, a negative regulator of neuron-intrinsic growth potential. The overall approach is to study the responses of axons to injury in mice lacking one or more growth regulators so the normal function of these proteins can be assessed.
Aim 1 will determine the cell type that is important for the role of Nogo in axon sprouting of the corticospinal tract (CST), whether Nogo and OMgp synergize to prevent CST axon sprouting, and will further explore the functional consequences of such enhanced sprouting in conjunction with rehabilitation.
Aim 2 will determine the combined effect of targeting the myelin inhibitor(s) and PTEN on spinal axon sprouting and regeneration, and whether enhanced axonal growth leads to synapse formation and functional recovery. The proposal takes advantage of the power of mouse genetics to pinpoint the role of specific intrinsic and extrinsic regulators and will likely yield important insights on the functions of these molecules in injury-induced axonal growth. A better understanding of the molecular determinants of injury-induced axonal growth in the adult CNS is crucial to the design of effective therapeutic strategies for various neurological conditions including spinal cord injury.

Public Health Relevance

The proposed study will provide important insight on the role of myelin inhibitors and PTEN in spinal axon regeneration and sprouting. Understanding the role of these extrinsic and intrinsic regulators of axonal repair is crucial to the design of effective therapeutic intervention to promote CNS repair following brain and spinal cord injury, stroke and related neurological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054734-07
Application #
8448251
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2006-04-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$327,196
Indirect Cost
$116,102
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Meifan; Geoffroy, Cédric G; Wong, Hetty N et al. (2016) Leucine Zipper-bearing Kinase promotes axon growth in mammalian central nervous system neurons. Sci Rep 6:31482
Geoffroy, Cédric G; Hilton, Brett J; Tetzlaff, Wolfram et al. (2016) Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System. Cell Rep 15:238-46
Geoffroy, Cédric G; Meves, Jessica M; Zheng, Binhai (2016) The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms. Neurosci Lett :
Lorenzana, Ariana O; Lee, Jae K; Mui, Matthew et al. (2015) A surviving intact branch stabilizes remaining axon architecture after injury as revealed by in vivo imaging in the mouse spinal cord. Neuron 86:947-54
Geoffroy, Cédric G; Lorenzana, Ariana O; Kwan, Jeffrey P et al. (2015) Effects of PTEN and Nogo Codeletion on Corticospinal Axon Sprouting and Regeneration in Mice. J Neurosci 35:6413-28
Meves, Jessica M; Zheng, Binhai (2014) Extrinsic inhibitors in axon sprouting and functional recovery after spinal cord injury. Neural Regen Res 9:460-1
Geoffroy, Cédric G; Zheng, Binhai (2014) Myelin-associated inhibitors in axonal growth after CNS injury. Curr Opin Neurobiol 27:31-8
Lemmon, Vance P; Ferguson, Adam R; Popovich, Phillip G et al. (2014) Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments. J Neurotrauma 31:1354-61
Chen, Meifan; Zheng, Binhai (2014) Axon plasticity in the mammalian central nervous system after injury. Trends Neurosci 37:583-93
Dickendesher, Travis L; Baldwin, Katherine T; Mironova, Yevgeniya A et al. (2012) NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat Neurosci 15:703-12

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